Treatments for dengue: a Global Dengue Alliance to address unmet needs
Journal: The Lancet Global Health (2023)

Dengue is currently the most rapidly spreading mosquito-borne viral infection in the world, with half of the world's population at risk of becoming infected.1WHOGeographical expansion of cases of dengue and chikungunya beyond the historical areas of transmission in the Region of the Americas.https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON448Date: March 23, 2023Date accessed: June 12, 2023Google Scholar As a result of climate change, rapid urbanisation, and widespread international travel, the incidence of dengue is rapidly increasing, overwhelming health-care systems in many lower-income countries. Climate change has increased the burden of dengue in endemic countries and has also led to expansion of this infection to new territories in Europe and North America.2Colón-González FJ Sewe MO Tompkins AM et al.Projecting the risk of mosquito-borne diseases in a warmer and more populated world: a multi-model, multi-scenario intercomparison modelling study.Lancet Planet Health. 2021; 5: e404-e414Summary Full Text Full Text PDF PubMed Scopus (79) Google Scholar Dengue is estimated to infect approximately 390 million individuals annually, with 96 million infections being symptomatic.1WHOGeographical expansion of cases of dengue and chikungunya beyond the historical areas of transmission in the Region of the Americas.https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON448Date: March 23, 2023Date accessed: June 12, 2023Google Scholar So far, the only strategy adopted to reduce the burden of dengue is vector control. Although techniques such as using Wolbachia bacteria to reduce dengue transmission by Aedes mosquitoes look promising,3Utarini A Indriani C Ahmad RA et al.Efficacy of Wolbachia-infected mosquito deployments for the control of dengue.N Engl J Med. 2021; 384: 2177-2186Crossref PubMed Scopus (155) Google Scholar it is evident that vector control alone is unlikely to be adequate to reduce the burden of dengue. The currently available dengue vaccines (CYD-TDV and TAK-003) have been shown to reduce hospitalisations, especially in dengue-seropositive individuals, but lack efficacy against some dengue virus serotypes.4Biswal S Borja-Tabora C Martinez Vargas L et al.Efficacy of a tetravalent dengue vaccine in healthy children aged 4–16 years: a randomised, placebo-controlled, phase 3 trial.Lancet. 2020; 395: 1423-1433Summary Full Text Full Text PDF PubMed Scopus (99) Google Scholar Furthermore, CYD-TDV showed a higher incidence of severe dengue in dengue-naive vaccine recipients, and both vaccines show some degree of waning immunity with time, especially in seronegative individuals.5Thomas SJ Is new dengue vaccine efficacy data a relief or cause for concern?.NPJ Vaccines. 2023; 8: 55Crossref Scopus (2) Google Scholar, 6Hadinegoro SR Arredondo-García JL Capeding MR et al.Efficacy and long-term safety of a dengue vaccine in regions of endemic disease.N Engl J Med. 2015; 373: 1195-1206Crossref PubMed Scopus (772) Google Scholar Therefore, an integrated approach that comprises vector control, use of safe and effective vaccines, and an effective treatment is needed to face the growing challenges of dengue infection. Efforts focused on finding a treatment have been scarce, with some investigator-led clinical trials conducted, and a few performed by pharmaceutical companies.7Troost B Smit JM Recent advances in antiviral drug development towards dengue virus.Curr Opin Virol. 2020; 43: 9-21Crossref Scopus (48) Google Scholar, 8Biering SB Harris E A step towards therapeutics for dengue.Nature. 2021; 598: 420-421Crossref Scopus (3) Google Scholar The importance of developing a treatment for dengue has largely been ignored.9Palanichamy Kala M St John AL Rathore APS Dengue: update on clinically relevant therapeutic strategies and vaccines.Curr Treat Options Infect Dis. 2023; 15: 27-52Crossref Google Scholar The Drugs for Neglected Diseases initiative, which is focused on finding novel affordable treatment solutions for neglected tropical diseases since its inception in 2003, has recently formed a Global Dengue Alliance with several institutions in dengue-endemic countries, including the Faculty of Medicine at Siriraj Hospital, Mahidol University in Thailand; the Ministry of Health in Malaysia; the Translational Health Science and Technology Institute in India; the Oswaldo Cruz Foundation in Brazil; and the Federal University of Minas Gerais in Brazil. The mission of this alliance is to accelerate research and development and deliver dengue therapeutics through an inclusive partnership. It aims to deliver a new treatment for dengue, within 5 years, from repurposed drugs and combinations (including novel antivirals from pharmaceutical companies). This alliance is co-created, co-owned, and co-funded by dengue-endemic countries, with a tiered governance mechanism allowing collaborative decision making at different levels. The organisations have formed a preclinical working group, a clinical working group, and a translational working group for effective communication and scientific planning. All three working groups feed into the Joint Steering Committee, which is responsible for delivering on the vision and mission of the alliance. The partners of this alliance share knowledge, experience, technologies, and capabilities to jointly validate preclinical assays with the ambition in the initial phase to identify currently available drugs that can be repurposed for use as dengue therapeutics. In parallel, clinical trials for these drug candidates are being designed using the expertise of clinicians in these countries who have been treating patients with dengue for many years, with initiation planned by the end of 2023. Formation of this alliance is a major step towards developing a treatment for dengue, by aggregating resources from endemic countries, and ensuring engagement, scientific leadership, clinical guidance, and political interest in these countries. The different working groups and the steering committee coordinate efforts to address gaps in knowledge, such as epidemiology (specifically in Africa), biomarkers and diagnostics, clinical trials, and regulatory framework, while promoting open science. Although currently the alliance has a small number of partners, it is open to collaborations with new partners and key stakeholders in therapeutics and diagnostics. Working with and aligning many partners and stakeholders to deliver objectives in a new model of collaboration is challenging, as is filling the existing knowledge gaps and need for integration, and leveraging information from different geographies and epidemiological settings. Furthermore, doing clinical trials aimed at treating dengue disease is challenging due to the seasonal nature of the disease, and with climate change, disease patterns could become more unpredictable. Although this approach is likely to accelerate development of a treatment, funding remains a challenge. With climate change becoming more of a concern in high-income countries, there is an increasing possibility that many global funding organisations will acknowledge the true burden of dengue, the devastation it causes to health systems and patients in endemic countries, and, therefore, the importance of funding initiatives to accelerate the development of new treatments for dengue. We declare no competing interests.